Currently, the standard treatment of T cell acute lymphoblastic leukemia (T-ALL) patients is intensive chemotherapy with almost 70% 5-year event free survival for pediatric and 50% for adult T-ALL patients. Moreover, such non-targeted therapies fail to address high-risk T-ALL subtypes. Unfortunately, recent attempts to introduce targeted therapies were plagued by both toxicity and resistance, further underlining the urgency for new treatments that also deal with leukemia-initiating cells (LIC) leading to complete disease remission. During the last funding period we were able to make important steps towards the understanding of the role of the ubiquitin system in acute lymphoblastic leukemia (ALL). We were able to identify somatic mutations on Fbw7, a ubiquitin ligase, in a large fraction of T cell ALL patients. We were able to show that Fbw7 can ubiquitinate and degrade NOTCH1 and MYC, two of the most important oncogenes in T-ALL. Using conditional Fbw7 alleles and were able to prove in vivo its role as a tumor suppressor. More recently we generated animals that expressed the exact Fbw7 mutations found in T-ALL patients and we were able to show that such missense mutations are able to directly expand leukemia initiating cells (LIC) but at the same time space normal hematopoiesis, providing an explanation on the selection of such mutations in this disease. Further analysis has shown that Fbw7 mutations expand LIC by aberrantly increasing the half-life of MYC. Moreover, conditional MYC deletions lead to LIC targeting and complete disease eradication opening the way for therapeutic targeting of T-ALL stem cells. Indeed, preliminary studies described here show that bromodomain and extra-terminal (BET) inhibitors can efficiently target MYC transcription and lead to suppression of growth in human T-ALL lines and primary cells. In this renewal application we would like to take advantage of all these significant developments and take our studies all the way from basic understanding of leukemia stem cell biology and the impact of FBW7 mutations to the identification of novel drugs that can target initiation and progression of this devastating tumor that frequently afflicts children and adolescents.